Molecular mechanisms of TGF-β antagonism by interferon γ and cyclosporine A in lung fibroblasts
Molecular mechanisms of TGF-β antagonism by interferon γ and cyclosporine A in lung fibroblasts
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DOI：
10.1096/fj.00-0233com
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发表时间：
2001-03-01
期刊：
影响因子：
4.8
通讯作者：
Roth, M
中科院分区：
文献类型：
--
作者：
Eickelberg, O;Pansky, A;Roth, M
肺纤维化是与转化生长因子β（TGF-β）活性增加相关的过量细胞外基质（ECM）沉积的致命病症。尽管对其病理特征了解很多，但我们对导致ECM和胶原沉积增加的信号转导途径的理解仍然不完全确定。我们以前曾报道过转录因子AP-1的JunD同源二聚体在肺成纤维细胞中被TGF-β特异性激活。在这里，我们证明了JunD也是TGF-β诱导效应所必需的。在原代人肺成纤维细胞中，针对JunD的反义而非c-fos或c-jun显著抑制胶原沉积对TGF-β的响应。然后，我们研究了药理学试剂抑制TGF-β诱导的信号传导和胶原沉积的能力。Cs-A和IFN-γ，而不是糖皮质激素，环磷酰胺，或硫唑嘌呤，抑制TGF-β诱导的信号，通过荧光素酶报告基因测定，和胶原蛋白沉积的评估。如电泳迁移率变化分析所示，Cs-A的TGF-β拮抗作用与JunD活化的直接抑制相关。相反，IFN-γ的作用需要信号转导和转录激活因子（STAT）-1。因此，我们确定AP-1的JunD同种型是肺成纤维细胞中TGF-β诱导效应的重要介质。TGF-β诱导的信号传导和胶原沉积被Cs-A和IFN-γ治疗有效地拮抗，这两者都表现出不同的分子作用机制。因此，这些观察结果为纤维化肺病的未来治疗提供了新的靶点。
Lung fibrosis is a fatal condition of excess extracellular matrix (ECM) deposition associated with increased transforming growth factor beta (TGF-beta) activity. Although much is known about its pathological features, our understanding of the signal transduction pathways resulting in increased ECM and collagen deposition in response to TGF-beta is still incompletely defined. We have previously reported that a JunD homodimer of the transcription factor AP-1 is specifically activated by TGF-beta in lung fibroblasts. Here we demonstrate that JunD is also specifically required for TGF-beta -induced effects. Antisense against JunD, but not c-fos or c-jun, significantly inhibited collagen deposition in response to TGF-beta in primary human lung fibroblasts. We then investigated the ability of pharmacological agents to inhibit TGF-beta -induced signaling and collagen deposition. Cs-A and IFN-gamma, but not glucocorticoids, cyclophosphamide, or azathioprine, inhibited TGF-beta -induced signaling, as assessed by luciferase reporter gene assays, and collagen deposition. TGF-beta antagonism by Cs-A was associated with direct inhibition of JunD activation, as demonstrated by electrophoretic mobility shift analyses. In contrast, the effects of IFN-gamma required signal transducer and activator of transcription (STAT)-1. We thus identify the JunD isoform of AP-1 as an essential mediator of TGF-beta -induced effects in lung fibroblasts. TGF-beta -induced signaling and collagen deposition are efficiently antagonized by Cs-A and IFN-gamma treatment, both of which exhibit distinct molecular mechanisms of action. These observations therefore offer novel targets for future therapy of fibrotic lung disease.